CD1 molecules are a third category of antigen presenting molecules, distinct from the MHC class I and class II molecules. A distinguishing feature of CD1 molecules is their ability to present lipid-containing antigens. Several different types of T cells can respond to CD1, including the NK T cells, a distinct lymphocyte subset that express both T cell antigen receptors (TCRs) and NK receptors. CD1 autoreactivity by NK T cells is greatly augmented by the addition of the lipoglycan alpha galactosyl ceramide (alphaGalCer). A distinguishing feature of NK T cells is their ability to rapidly secreted large amounts of cytokines following antigen stimulation. NK T cells, and the cytokines they secreted have been implicated as important elements controlling a variety of immune responses, including the response to tumors. NK T cells also have been implicated in preventing autoimmune disease progression, particularly for diabetes in animal models as well as in patients. This application is concerned with the antigen presenting function of CD1d molecules, and in particular, how the interaction of CD1d with lipid antigens and T cell antigen receptors (TCRs) is important in determining how the cytokine output from NK T cells and their in vivo behavior We will employ site directed mutagenesis of mouse CD1.1 (mCD1), in order to define how mCD1 can stimulate autoreactive, T cells and present both lipid and peptide antigens. Finally, we will explore how these molecular interactions alter the development of diabetes in NOD mice. In summary, the experiments are designed to achieve a better understanding of how the secretion of cytokines by NK T cells is controlled. Suck knowledge could lead to novel immune therapies for cancer and autoimmune disease.